The present invention relates to the fields of medicine and pharmacy and particularly to providing effective taste masked dosage forms which facilitate compliance by patients.
Patients who will not or cannot swallow, such as young children, the very elderly and patients with dysphagia constitute a significant challenge to the pharmaceutical industry. The industry has met that challenge by developing a number of drug delivery protocols, including rapid in-mouth disintegrating tablets, tablets which disintegrate in liquid prior to ingestion, liquids and syrups, gums and even transdermal patches. Unfortunately, each of these methods can pose their own problems.
Transdermal patches can be inconvenient or uncomfortable. They can also be quite expensive to produce. The flux of drug through the skin can also raise very complex dosing issues. Liquids are particularly useful for children. However, liquids can be inconvenient for adults and can be relatively expensive to formulate, package and transport. Tablets which can be dissolved in a liquid before ingestion can also be useful. However, they can also be quite inconvenient in that they require that a liquid and drinking container be provided. Time is required for disintegration or dissolution even when effervescent tablets are used. Finally, these materials can be quite a mess as they can leave a particulate and/or scum in the glass. In-mouth disintegrable dosage forms such as chewables and self disintegrating tablets offer great convenience. Self disintegrating tablets and/or chewables, however, present real taste masking problems as the act of chewing can disrupt protective coatings. They are of ten very soft, making it difficult and expensive to formulate, package and store. In addition, particularly as compared to tablets which are swallowed, taste masking can become a significant obstacle due to the length of exposure in the patient""s mouth.
Of course, there are a variety of ways of taste masking various drugs. These include the use of flavorings, sweeteners, effervescent systems and various coating strategies. But for certain drugs and in particular antibiotics, such as gatifloxacin, traditional taste masking has not proven sufficiently effective. In addition, some of these taste masking strategies cannot adapt well to the demands of rapidly dissolvable dosage forms and/or can be quite expensive.
Modified celluloses such as hydroxypropylmnethyl-cellulose (HPMC), ethylcelluloses and mixtures of such celluloses have been used to produce enteric coatings as well as coatings which can provide a controlled drug release. Controlled release means either an extended release or a rapid release in the small intestine. Such coatings have also be used in taste masking. For many drugs they are acceptable not only for taste masking but also for providing a desired release. However, such coatings were found to be ineffective when it came toe orally disintegrating tablets containing gatifloxacin. Without wishing to be bound by a particular theory of operation, it is believed that, when exposed to saliva in the mouth during the disintegration of the tablet, at least a portion of the coating dissolves or swells, thereby exposing the offending drug to the patient""s taste buds. Another product, Eudragit E100 which is a mixture of methylaminoethyl methacrylate and neutral methacrylic acid ester has also been known for use in taste masking, particularly in combination with celluloses such as a cellulose esters. However, these mixtures, as well as Eudragit E100 alone, were found to be ineffective in providing taste asking when using certain objectionable tasting drugs. Therefore there still remains a need for effective taste masking strategies, particularly for use with aggressively bad tasting drugs, which lend themselves to in-mouth rapidly dissolving dosage forms.
The present invention relates to the discovery of a coating system useful for completely taste masking objectionable tasting drugs. In a preferred embodiment, the taste masking is accomplished without significantly altering the release and availability of the drug.
In accordance with the present invention, there is provided a taste masked formulation which includes a taste masked formulation which rapidly releases in the stomach of a patient comprising:
A drug containing core;
A taste masking layer composed of a material which is generally insoluble in saliva at a neutral to basic pH and completely soluble in saliva at a pH of less than about 6.5; and
A spacing layer surrounding said core and substantially completely sequestering said core from said taste masking layer; said taste masking layer preventing exposure of said spacing layer in the mouth of a patient for a period of at least about 20 seconds after being placed into the mouth.
The taste masking layer must be capable of rapidly exposing the spacing layer when the formulation reaches the patient""s stomach. In a particularly preferred embodiment, the taste masked formulation is a rapid release formulation capable of rapidly exposing the contents of the core when introduced to the patient""s stomach.
Merely applying thicker layers of coating materials can be an ineffective method of taste masking certain objectionable drugs. Thick coatings can cause problems both in terms of size and cost. They can also raise problems in that they may interfere with the desired release profile of the drug. It has been found, however, that by coordinating the right types of coating materials, it is possible to completely mask the taste of particularly objectionable drugs while, at the same time, not adversely affecting the intended drug release profile. This is particularly critical in the context of rapid release dosage forms. By xe2x80x9crapid release,xe2x80x9d it is understood that the taste masking system should provide little or no interference with the solubility and bioavailability of the drug when compared to the same drug administered in, for example, elixir or solution form.
The use of a spacing layer in combination with a taste masking layer has been found to be particularly effective. Without wishing to be bound by any particular theory, it is believed that drugs, even granulated formulations, can interfere with taste masking coatings. Fines, abrasions, variable coating thickness and the like can all lead to situations where the taste mask coating is compromised. With certain aggressively bad tasting drugs, even a little exposure is too much. This is particularly problematic where the taste mask coating used is one which is designed to dissolve rapidly at acidic pHs. When such coatings are held in the mouth of a patient during the tablet""s disintegration, a neutral to slightly acidic pH can sufficiently undermine taste masking so as to expose the patient to objectionable tasting drugs. Using a spacing layer to substantially sequester the drug from the taste masking layer helps reduce or eliminate such coating imperfections. It also acts to delay contact between the drug and the taste buds of a patient upon partial or total failure of the taste masking layer in the patient""s mouth. There is also provided a dosage form which includes a dosage form intended for direct oral administration, comprising: an effective amount of at least one drug, said drug present in the cores of coated particles, said cores including a taste masking layer composed of a material which is generally insoluble in saliva at a neutral to basic pH and completely soluble in saliva at a pH of less than about 6.5 and a spacing layer surrounding said core and substantially completely sequestering said core from said taste masking layer; said taste masking layer preventing exposure of said spacing layer in the mouth of a patient for a period of at least about 20 seconds after being placed into the mouth; and at least one pharmaceutically acceptable excipient provided in an amount of between greater than zero and about 100%, based on the weight of the finished dosage form.